The impact of microglial activation on blood-brain barrier in brain diseases

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine.

Download Full-text

Blood-Brain Barrier Transport of Drugs for the Treatment of Brain Diseases

CNS & Neurological Disorders - Drug Targets ◽

10.2174/187152709788680652 ◽

2009 ◽

Vol 8 (3) ◽

pp. 195-204 ◽

Cited By ~ 27

Author(s):

Reinhard Gabathuler

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Diseases ◽

Blood Brain

Download Full-text

Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽

10.3390/pharmaceutics13060892 ◽

2021 ◽

Vol 13 (6) ◽

pp. 892

Author(s):

Elisa L. J. Moya ◽

Elodie Vandenhaute ◽

Eleonora Rizzi ◽

Marie-Christine Boucau ◽

Johan Hachani ◽

...

Keyword(s):

Drug Discovery ◽

Blood Brain Barrier ◽

Early Stage ◽

Molecular Transport ◽

Brain Barrier ◽

Blood Brain ◽

Cns Drugs ◽

The Impact ◽

The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

Download Full-text

Can Natural Products Exert Neuroprotection without Crossing the Blood–Brain Barrier?

International Journal of Molecular Sciences ◽

10.3390/ijms22073356 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3356

Author(s):

Manon Leclerc ◽

Stéphanie Dudonné ◽

Frédéric Calon

Keyword(s):

Natural Products ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Diseases ◽

Omega 3 ◽

Indirect Pathway ◽

Brain Functions ◽

Blood Brain ◽

The Central Nervous System ◽

Peripheral Metabolism

The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood–brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut–microbiota–brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer’s disease.

Download Full-text

CdSe/ZnS Core-Shell-Type Quantum Dot Nanoparticles Disrupt the Cellular Homeostasis in Cellular Blood–Brain Barrier Models

International Journal of Molecular Sciences ◽

10.3390/ijms22031068 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1068

Author(s):

Katarzyna Dominika Kania ◽

Waldemar Wagner ◽

Łukasz Pułaski

Keyword(s):

Gene Expression ◽

Quantum Dot ◽

Blood Brain Barrier ◽

Protein Gene ◽

Brain Barrier ◽

Core Shell ◽

Cellular Homeostasis ◽

Blood Brain ◽

Shell Type ◽

The Impact

Two immortalized brain microvascular endothelial cell lines (hCMEC/D3 and RBE4, of human and rat origin, respectively) were applied as an in vitro model of cellular elements of the blood–brain barrier in a nanotoxicological study. We evaluated the impact of CdSe/ZnS core-shell-type quantum dot nanoparticles on cellular homeostasis, using gold nanoparticles as a largely bioorthogonal control. While the investigated nanoparticles had surprisingly negligible acute cytotoxicity in the evaluated models, a multi-faceted study of barrier-related phenotypes and cell condition revealed a complex pattern of homeostasis disruption. Interestingly, some features of the paracellular barrier phenotype (transendothelial electrical resistance, tight junction protein gene expression) were improved by exposure to nanoparticles in a potential hormetic mechanism. However, mitochondrial potential and antioxidant defences largely collapsed under these conditions, paralleled by a strong pro-apoptotic shift in a significant proportion of cells (evidenced by apoptotic protein gene expression, chromosomal DNA fragmentation, and membrane phosphatidylserine exposure). Taken together, our results suggest a reactive oxygen species-mediated cellular mechanism of blood–brain barrier damage by quantum dots, which may be toxicologically significant in the face of increasing human exposure to this type of nanoparticles, both intended (in medical applications) and more often unintended (from consumer goods-derived environmental pollution).

Download Full-text

Gastrodia-Uncaria Water Extract Inhibits Endoplasmic Reticulum Stress and Matrix Metalloproteinase in Protecting against Cerebral Ischemia

10.1101/2021.07.21.452303 ◽

2021 ◽

Author(s):

Angus Y Choi ◽

Jia Wen Xian ◽

Sum Yi Ma ◽

Zhixiu Lin ◽

Chun Wai Chan

Keyword(s):

Endoplasmic Reticulum ◽

Cerebral Ischemia ◽

Endoplasmic Reticulum Stress ◽

Blood Brain Barrier ◽

Neuroprotective Effect ◽

Water Extract ◽

Neuronal Cell ◽

Brain Barrier ◽

Brain Diseases ◽

Blood Brain

Stroke is the second leading cause of death in worldwide, in which cerebral ischemia accounts for 87% of all cases. The building up of endoplasmic reticulum stress in cerebral ischemia contributes to the disruption of blood brain barrier and neuronal cell death. The only FDA-approved drug, recombinant tissue plasminogen activator, is still of limited use due to the narrow window period and lack of neuroprotective effect. Therefore, it is necessary to explore alternative treatment on cerebral ischemia. Tianma-Gouteng decoction is a traditional Chinese Medicine prescription used to treat brain diseases in China. In this study, we investigated the neuroprotective effect of a water extract consisting of Gastrodia elata and Uncaria rhynchophylla, which are the two main herbs in the decoction. Cerebral ischemia was induced in rats using middle cerebral artery occlusion. GUW-treated rats have significantly reduced infarction volume and recovered neurological functions. The number of protein aggregates and caspase-12 positive cells were significantly inhibited. In vitro oxygen-glucose deprivation / reoxygenation stroke model demonstrated that the unfolded protein response proteins GRP78 and PDI were upregulated by GUW. Less ubiquitin puncta and normalized ubiquitin distribution indicated the reduction in endoplasmic reticulum stress. Furthermore, a lower Evan blue signal and MMPsense signal was observed, suggesting that GUW may preserve the blood brain barrier integrity through inhibiting MMP activity. Taken together, this suggested that GUW protected ischemic neurons and the blood brain barrier through inhibiting endoplasmic reticulum stress.

Download Full-text

Targeting microRNAs to Regulate the Integrity of the Blood–Brain Barrier

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.673415 ◽

2021 ◽

Vol 9 ◽

Author(s):

Juntao Wang ◽

Fang Xu ◽

Xiaoming Zhu ◽

Xianghua Li ◽

Yankun Li ◽

...

Keyword(s):

Blood Brain Barrier ◽

Neurovascular Unit ◽

Cerebrovascular Diseases ◽

Brain Parenchyma ◽

Brain Barrier ◽

Brain Diseases ◽

Blood Brain ◽

Recent Developments ◽

Important Regulator

The blood–brain barrier (BBB) is a highly specialized neurovascular unit that protects the brain from potentially harmful substances. In addition, the BBB also engages in the exchange of essential nutrients between the vasculature and brain parenchyma, which is critical for brain homeostasis. Brain diseases, including neurological disorders and cerebrovascular diseases, are often associated with disrupted BBB integrity, evidenced by increased permeability. Therefore, defining the mechanisms underlying the regulation of BBB integrity is crucial for the development of novel therapeutics targeting brain diseases. MicroRNAs (miRNA), a type of small non-coding RNAs, are emerging as an important regulator of BBB integrity. Here we review recent developments related to the role of miRNAs in regulating BBB integrity.

Download Full-text

Intracerebral Hemorrhage and Diabetes Mellitus: Blood-Brain Barrier Disruption, Pathophysiology, and Cognitive Impairments

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210223145112 ◽

2021 ◽

Vol 20 ◽

Author(s):

Ghaith A. Bahadar ◽

Zahoor A Shah

Keyword(s):

Diabetes Mellitus ◽

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Comorbid Condition ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption ◽

The Impact

: There is a surge in diabetes incidence with an estimated 463 million individuals been diagnosed worldwide. Diabetes Mellitus (DM) is a major stroke-related comorbid condition that increases the susceptibility of disabling post-stroke outcomes. Although less common, intracerebral hemorrhage (ICH) is the most dramatic subtype of stroke that is associated with higher mortality, particularly in DM population. Previous studies have focused mainly on the impact of DM on ischemic stroke. Few studies have focused on impact of DM on ICH and discussed the blood-brain barrier disruption, brain edema, and hematoma formation. However, more recently, investigating the role of oxidative damage and reactive oxygen species (ROS) production in preclinical studies involving DM-ICH animal models has gained attention. But, little is known about the correlation between neuroinflammatory processes, glial cells activation, and peripheral immune cell invasion with DM-ICH injury. DM and ICH patients experience impaired abilities in multiple cognitive domains by relatively comparable mechanisms, which could get exacerbated in the setting of comorbidities. In this review, we discuss both the pathology of DM as a comorbid condition for ICH and the potential molecular therapeutic targets for the clinical management of the ICH and its recovery.

Download Full-text

Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/2936737 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 9

Author(s):

Zi-xian Chen ◽

Qing-qing Xu ◽

Chun-shuo Shan ◽

Yi-hua Shi ◽

Yong Wang ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Ischemic Injury ◽

Brain Barrier ◽

Brain Diseases ◽

Glycoprotein P ◽

Blood Brain ◽

Cerebral Ischemic Injury ◽

Bbb Permeability ◽

Cerebral Ischemic

Borneol, a natural product in the Asteraceae family, is widely used as an upper ushering drug for various brain diseases in many Chinese herbal formulae. The blood-brain barrier (BBB) plays an essential role in maintaining a stable homeostatic environment, while BBB destruction and the increasing BBB permeability are common pathological processes in many serious central nervous system (CNS) diseases, which is especially an essential pathological basis of cerebral ischemic injury. Here, we aimed to conduct a systematic review to assess preclinical evidence of borneol for experimental ischemic stroke as well as investigate in the possible neuroprotective mechanisms, which mainly focused on regulating the permeability of BBB. Seven databases were searched from their inception to July 2018. The studies of borneol for ischemic stroke in animal models were included. RevMan 5.3 was applied for data analysis. Fifteen studies investigated the effects of borneol in experimental ischemic stroke involving 308 animals were ultimately identified. The present study showed that the administration of borneol exerted a significant decrease of BBB permeability during cerebral ischemic injury according to brain Evans blue content and brain water content compared with controls (P<0.01). In addition, borneol could improve neurological function scores (NFS) and cerebral infarction area. Thus, borneol may be a promising neuroprotective agent for cerebral ischemic injury, largely through alleviating the BBB disruption, reducing oxidative reactions, inhibiting the occurrence of inflammation, inhibiting apoptosis, and improving the activity of lactate dehydrogenase (LDH) as well as P-glycoprotein (P-GP) and NO signaling pathway.

Download Full-text

Photodynamic Opening of the Blood–Brain Barrier Using Different Photosensitizers in Mice

Applied Sciences ◽

10.3390/app10010033 ◽

2019 ◽

Vol 10 (1) ◽

pp. 33 ◽

Cited By ~ 1

Author(s):

Oxana Semyachkina-Glushkovskaya ◽

Ekaterina Borisova ◽

Vanya Mantareva ◽

Ivan Angelov ◽

Ivelina Eneva ◽

...

Keyword(s):

Tight Junction ◽

Blood Brain Barrier ◽

Confocal Imaging ◽

Brain Barrier ◽

Zinc Phthalocyanine ◽

Brain Diseases ◽

Blood Brain ◽

Age Related ◽

Dextran 70 ◽

The Brain

In a series of previous studies, we demonstrated that the photodynamic therapy (PDT), as a widely used tool for treatment of glioblastoma multiforme (GBM), also site-specifically opens the blood–brain barrier (BBB) in PDT-dose and age-related manner via reversible disorganization of the tight junction machinery. To develop the effective protocol of PDT-opening of the BBB, here we answer the question of what kind of photosensitizer (PS) is the most effective for the BBB opening. We studied the PDT-opening of the BBB in healthy mice using commercial photosensitizers (PSs) such as 5-aminolevulenic acid (5-ALA), aluminum phthalocyanine disulfonate (AlPcS), zinc phthalocyanine (ZnPc) and new synthetized PSs such as galactose functionalized ZnPc (GalZnPc). The spectrofluorimetric assay of Evans Blue albumin complex (EBAC) leakage and 3-D confocal imaging of FITC-dextran 70 kDa (FITCD) extravasation clearly shows a revisable and dose depended PDT-opening of the BBB to EBAC and FITCD associated with a decrease in presence of tight junction (TJ) in the vascular endothelium. The PDT effects on the BBB permeability, TJ expression and the fluorescent signal from the brain tissues are more pronounced in PDT-GalZnPc vs. PDT-5-ALA/AlPcS/ZnPc. These pre-clinical data are the first important informative platform for an optimization of the PDT protocol in the light of new knowledge about PDT-opening of the BBB for drug brain delivery and for the therapy of brain diseases.

Download Full-text